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PubMed2003

Ecological validity of a simplified version of the multiple errands shopping test.

Shallice and Burgess (1991) reported the utility of the Multiple Errands Test (MET) in discriminating executive deficits in three frontal lobe patients with preserved high IQ, who were otherwise unimpaired on tests of executive function. The aim of this study was to ascertain the value of a simplified version of the MET (MET-SV) for use with the range of people more routinely encountered in clinical practice. Main findings were as follows: 1) The test discriminated well between neurological patients and controls, and the group effects remained when the difference in current general cognitive functions (WAIS-R FSIQ) was taken into account. 2) The best predictors of performance in the healthy control group (n = 46) were age and the number of times participants asked for help (with more requests associated with poorer performance). 3) In the neurological group, two clear patterns of failure emerged, with performance either characterized by rule breaking or failure to achieve tasks. These two patterns were associated with different dysexecutive symptoms in everyday life. 4) The patients not only made more errors than controls, but also different ones. A scoring method that took this into account markedly increased test sensitivity. 5) Many patients passed traditional tests of executive frontal lobe function but still failed the MET-SV. This pattern was strongly associated with observed dysexecutive symptoms in everyday life. The results demonstrate the clinical utility of the test, and suggest that there are two common and independent sources of failure on multitasking tests in a general neurological population: memory dysfunction, and initiation problems.

Adult↗

PubMed1999

Application of biological monitoring to the quantitative exposure assessment for neuropsychological effect by chronic exposure to organic solvents.

OBJECTIVE: Quantitative exposure assessment became more common as a result of attempts to reduce nondifferential exposure misclassification and to observe a steeper exposure-response relationship. Several exposure variables were compared in a demonstration of the exposure-response relationship between neuropsychological abnormality and long-term exposure to organic solvents in workers at one shipyard. METHOD: Environmental monitoring and biological monitoring were performed to evaluate the exposure of the workers to organic solvents. Cumulative exposure (CE) and lifetime-weighted average exposure variables were developed with both environmental and biological monitoring data. A neuropsychological questionnaire and a function test for confirmation of a disorder or dysfunction in attention, executive function, visuospatial, and constructional abilities, learning and memory, and psychomotor function were performed. RESULTS: The abnormal rate in neuropsychological diagnosis was 9.3% in the exposed group, which was much higher than the 2.1% rate obtained in the nonexposed group (P<0.01). The neuropsychological abnormal rate showed a significant dose-response association with CE created with biological monitoring data. The results also suggest that biological monitoring can provide impressive and effective information for quantitative exposure assessment, even in epidemiology studies.

Adult↗

PubMedDate not supplied

Long-term amnesia: a review and detailed illustrative case study.

Long-term amnesia is a slowly developing form of anterograde amnesia accompanied by retrograde amnesia of variable severity (Kapur, 1996; 1997) often associated with damage to the anterior temporal neocortex and epileptic seizures. The precise neural and functional deficits that underlie this condition are unknown. A patient, JL, who has this condition following a closed-head injury, is described in detail. Her injury caused bilateral anterior temporal neocortex damage that was more extensive on the left and right-sided damage to the perirhinal and orbitofrontal cortices. The hippocampus appeared to be intact bilaterally. Epilepsy developed within two years of JL's injury. Apart from her memory impairments, JL's cognitive functions, including high-level visual perception, attention, semantic memory and executive functions were well preserved. Her memory also seemed well preserved for at least 30 minutes following encoding. The one exception was the patient's relatively greater impairment at difficult visual recognition tests for which verbalization may not have been an effective strategy. This problem may have been caused by JL's right-sided perirhinal and orbitofrontal cortex damage. Her recall and recognition was clearly impaired after a three-week delay. She also showed a retrograde amnesia, which appeared to be milder than her remote post-morbid memory deficit. JL's remote memory was preserved for information first encountered in either the pre- or post-morbid period provided the information had received sufficient rehearsal over long periods of time. Her long-term amnesia may have been caused by anterior temporal neocortex damage, possibly in association with her epileptic seizures. Whether the condition is heterogeneous, involves a deficit in slow consolidation, disruption of unconsolidated memories, or blockage of maintenance or disruption of insufficiently rehearsed memories whether or not these have been slowly consolidated is discussed.

Adult↗

PubMed2001

Brain energy metabolism in Alzheimer's disease: 99mTc-HMPAO SPECT imaging during verbal fluency and role of astrocytes in the cellular mechanism of 99mTc-HMPAO retention.

The central hypothesis of the study which has been carried out as part of the NRP38 program, is that perturbations of brain energy metabolism are critically involved in the neurodegeneration occurring in Alzheimer's disease (AD) and that they may correlate with early cognitive dysfunctioning. In the present multidisciplinary study we set out to monitor brain energy metabolism using FDG-PET and HMPAO-SPECT imaging in a cohort of individuals over 65 years of age, drawn from the general population. HMPAO-SPECT imaging, which is a simpler and more widely accessible imaging procedure than FDG-PET, was performed under basal conditions and during the performance of a cognitive task (verbal fluency test). Three groups were studied. Two groups (groups I and II) included individuals age 65 or more, with no cognitive impairment and carrying an APOE4 positive or APOE4 negative phenotype, respectively; a third group (group III) included patients with clinical signs of AD. Each subject entering the study underwent an FDG-PET, an HMPAO-SPECT and an extensive battery of neuropsychological tests which assess various aspects of cognitive functioning, with a strong emphasis on working memory, divided attention and executive functions. A total of 101 participants were submitted to brain imaging and neuropsychological testing. Among these, 60 participants received the same set of imaging and neuropsychological tasks 24-36 months after the first set (phase II). In this article, we present a preliminary analysis performed on ten subjects from groups I and II and nine subjects from group III: activation (verbal fluency task) induced a specific pattern of increase in HMPAO retention (including BA 9/10, BA 18 bilaterally and right BA 17). In contrast to controls, in nine AD subjects no significant differences in HMPAO retention were observed when comparing activation and basal conditions. The cellular and molecular mechanisms that underlie the retention of HMPAO, the tracer used for single photon emission computed tomography (SPECT) imaging, has been studied in vitro in purified preparations of neurons and astrocytes with the aim of investigating the contribution of different cell types to hexamethyl-propyleneamineoxime labeled with technetium-99m (99mTc-HMPAO) retention in vitro. Results show that 99mTc-HMPAO retention predominates in astrocytes over neurons by a factor of approximately 2.5. Diethyl maleate, ethacrynic acid and buthionine sulfoximine, three agents which significantly reduce glutathione levels, also decreased 99mTc-HMPAO retention in both astrocytes and in neurons. Decrease did not always correlate with glutathione levels however, thus suggesting that other factors could be involved. The data presented indicate that astrocytes might constitute a prominent site of 99mTc-HMPAO retention and most likely contribute significantly to the SPECT signal. In addition, they also suggest that specific alterations in glial cell metabolism could explain flow-independent changes in 99mTc-HMPAO retention in the brain as observed by SPECT in certain pathologies (including Alzheimer's disease). In particular, these observations suggest a key role of astrocytes in the signal detected with the imaging procedure, which is altered in the Alzheimer's cohort subjected to the verbal fluency activation task.

Aged↗

PubMed2002

Effects on the brain of a psychological treatment: cognitive remediation therapy: functional magnetic resonance imaging in schizophrenia.

BACKGROUND: The results of one randomised control trial testing a psychological rehabilitation programme aimed at information processing strategies showed improvements in cognition post-treatment. AIMS: To determine whether there are concomitant brain activation changes as a result of engaging in cognitive remediation therapy (CRT). METHOD: Three groups (patients receiving control therapy or CRT and a healthy control group) were investigated in a repeated measures design using the two-back test. Functional magnetic resonance imaging (fMRI) data and a broad assessment of executive functioning were completed at baseline and post-treatment. Brain activation changes were identified after accounting for possible task-correlated motion artefact. RESULTS: fMRI analyses indicate that the control group showed decreased activation but the two patient groups showed an increase in activation over time. The patient group that received successful CRT had significantly increased brain activation in regions associated with working memory, particularly the frontocortical areas. CONCLUSIONS: This is the first time that brain activation changes in a seriously disabled group of patients with schizophrenia can be associated clearly with psychological rather than pharmacological therapy.

Adult↗

PubMed1999

Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a 4-year follow-up study.

In a prior study of 54 relatives of patients with schizophrenia and 72 control participants, 3 neuropsychological functions met the criteria for risk indicators of the schizophrenia genotype: executive functioning, memory, and auditory attention. In an assessment of the stability of these findings, the sample was reexamined 4 years after the initial assessment. Three test scores were found to differ between groups (Immediate Verbal Memory, Delayed Verbal Memory, and Dichotic Listening Digits Detected) or to show a significant Group x Gender interaction (immediate and delayed verbal and visual memories). None of the test scores showed Group x Time interactions, suggesting that the discriminating power of the tests was stable over time. Evidence for deficits in working memory and rule learning on the object alternation test was also found. These results support the idea that neuropsychological dysfunction among relatives of patients with schizophrenia is a stable trait caused by the familial predisposition to schizophrenia.

Adult↗

PubMed2000

Mood, personality, and self-monitoring: negative affect and emotionality in relation to frontal lobe mechanisms of error monitoring.

A fundamental question in frontal lobe function is how motivational and emotional parameters of behavior apply to executive processes. Recent advances in mood and personality research and the technology and methodology of brain research provide opportunities to address this question empirically. Using event-related-potentials to track error monitoring in real time, the authors demonstrated that variability in the amplitude of the error-related negativity (ERN) is dependent on mood and personality variables. College students who are high on negative affect (NA) and negative emotionality (NEM) displayed larger ERN amplitudes early in the experiment than participants who are low on these dimensions. As the high-NA and -NEM participants disengaged from the task, the amplitude of the ERN decreased. These results reveal that affective distress and associated behavioral patterns are closely related with frontal lobe executive functions.

Adolescent↗

PubMed2005

Apolipoprotein E and prospective memory in normally aging adults.

The epsilon4 allele of apolipoprotein E (APOE) is an established risk factor for Alzheimer's disease, despite uncertainty as to its effect on cognitive function in normal aging. Some evidence suggests poor episodic memory and executive functioning in epsilon4 allele carriers. Prospective memory has been overlooked in investigations of the relationship between APOE and cognition. The authors used a laboratory paradigm to examine the relationship between prospective memory and APOE status in healthy elderly adults, and they varied the association (high vs. low) between a target word and a response word. The authors found a significant deficit in prospective memory for epsilon4 allele carriers but no effect of association in either group. The results suggest the deficit was due to failure of the prospective component of the task.

Aged↗

PubMed1994

Cloning of mid-G1 serum response genes and identification of a subset regulated by conditional myc expression.

The emergence of cells from a quiescent G0 arrested state into the cell cycle is a multistep process that begins with the immediate early response to mitogens and extends into a specialized G1 phase. Many immediate early serum response genes including c-fos, c-myc, and c-jun are transcriptional regulators. To understand their roles in regulating cell cycle entry and progression, the identities of their regulatory targets must be determined. In this work we have cloned cDNA copies of messenger RNAs that are either up- or down-regulated at a mid-G1 point in the serum response (midserum-response [mid-SR]). The mid-SR panel is expected to include both direct and indirect targets of immediate early regulators. This expectation was confirmed by the identification of several transcriptional targets of conditional c-myc activity. In terms of cellular function, the mid-SR class is also expected to include execution genes needed for progression through G1 and into S-phase. DNA sequence data showed that the mid-SR panel included several genes already known to be involved in cell cycle progression or growth transformation, suggesting that previously unknown cDNAs in the same group are good candidates for other G1 execution functions. In functional assays of G0-->S-phase progression, c-myc expression can bypass the requirement for serum mitogens and drive a large fraction of G0 arrested cells through G1 into S-phase. However, beyond this general similarity, little is known about the relation of a serum-driven progression to a myc-driven progression. Using the mid-SR collection as molecular reporters, we found that the myc driven G1 differs qualitatively from the serum driven case. Instead of simply activating a subset of serum response genes, as might be expected, myc regulated some genes inversely relative to serum stimulation. This suggests that a myc driven progression from G0 may have novel properties with implications for its action in oncogenesis.

3T3 Cells↗

PubMed2000

An ontology for biological function based on molecular interactions.

MOTIVATIONS: A number of important bioinformatics computations involve computing with function: executing computational operations whose inputs or outputs are descriptions of the functions of biomolecules. Examples include performing functional queries to sequence and pathway databases, and determining functional equality to evaluate algorithms that predict function from sequence. A prerequisite to computing with function is the existence of an ontology that provides a structured semantic encoding of function. Functional bioinformatics is an emerging subfield of bioinformatics that is concerned with developing ontologies and algorithms for computing with biological function. RESULTS: The article explores the notion of computing with function, and explains the importance of ontologies of function to bioinformatics. The functional ontology developed for the EcoCyc database is presented. This ontology can encode a diverse array of biochemical processes, including enzymatic reactions involving small-molecule substrates and macromolecular substrates, signal-transduction processes, transport events, and mechanisms of regulation of gene expression. The ontology is validated through its use to express complex functional queries for the EcoCyc DB. CONTACT: pkarp@ai.sri.com

Computational Biology↗

PubMed2001

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.

Animals↗

PubMed2003

Cognitive function in post-treatment Lyme disease: do additional antibiotics help?

BACKGROUND: It is controversial whether additional antibiotic treatment will improve cognitive function in patients with post-treatment chronic Lyme disease (PTCLD). OBJECTIVE: To determine whether antibiotic therapy improves cognitive function in two randomized double-blind placebo-controlled studies of patients with PTCLD. METHODS: A total of 129 patients with a physician-documented history of Lyme disease from three study sites in the northeast United States were studied. Seventy-eight were seropositive for IgG antibodies against Borrelia burgdorferi, and 51 were seronegative. Patients in each group were randomly assigned to receive IV ceftriaxone 2 g daily for 30 days followed by oral doxycycline 200 mg daily for 60 days or matching IV and oral placebos. Assessments were made at 90 and 180 days after treatment. Symptom severity was measured from the cognitive functioning, pain, and role functioning scales of the Medical Outcomes Study (MOS). Memory, attention, and executive functioning were assessed using objective tests. Mood was assessed using the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory. RESULTS: There were no significant baseline differences between seropositive and seronegative groups. Both groups reported a high frequency of MOS symptoms, depression, and somatic complaints but had normal baseline neuropsychological test scores. The combined groups showed significant decreases in MOS symptoms, higher objective test scores, and improved mood between baseline and 90 days. However, there were no significant differences between those receiving antibiotics and placebo. CONCLUSION: Patients with post-treatment chronic Lyme disease who have symptoms but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo.

Administration, Oral↗

PubMed2004

The nature and course of neuropsychological morbidity in chronic temporal lobe epilepsy.

OBJECTIVE: To characterize the nature and degree of cognitive morbidity in patients with chronic temporal lobe epilepsy compared with healthy control subjects, determine the association between the duration of epilepsy and cognitive morbidity, and ascertain whether there are factors that moderate the association between duration of disorder and cognitive impairment. METHODS: Temporal lobe epilepsy (n = 96) and healthy control (n = 82) subjects were assessed with a comprehensive neuropsychological battery. Test performances were adjusted for age, gender, and education and transformed to a common metric (z scores). Analyses included group comparisons and correlations of duration of epilepsy with cognitive morbidity. RESULTS: Patients with temporal lobe epilepsy exhibited not only worse memory function (p < 0.05) but worse performance across measures of intelligence, language, executive function, and motor speed (p < 0.05). Chronicity of epilepsy was related to worsening mental status (r = 0.42, p < 0.001). This relationship was particularly evident among those individuals with less (r = 0.58, p < 0.001) compared with more (r = 0.25, NS) cerebral reserve, operationally defined by years of formal education. CONCLUSIONS: Neuropsychological morbidity in chronic temporal lobe epilepsy is widespread in nature despite a focal epileptic process. Cross-sectional analyses demonstrate that increasing duration of epilepsy is associated with worsening mental status. Individuals with less educational attainment (low cerebral reserve) exhibit especially poor cognitive function in association with chronicity of epilepsy.

Adolescent↗

PubMed2003

Visuospatial dysfunction in the neurodegenerative diseases.

Visuospatial dysfunction is not generally considered a cardinal feature of the common neurodegenerative disorders of late life like Alzheimer's disease (AD), Parkinson's disease (PD), and Dementia with Lewy bodies (DLB). However, a large number of research studies have shown visually related disorders to be surprisingly pervasive among these disease states. Broader recognition of the problems is hindered by a complex literature, which suffers from a lack of uniform definitions of what constitutes "visuospatial" dysfunction and few commonly accepted theoretical models for interpreting results. The interface between visual-spatial function and other variably-defined constructs such as attention and executive function further complicates experimental approaches to this construct. Nonetheless, this review addresses both theoretical and practical issues regarding the presence, importance, and correlates of visual dysfunction associated with neurodegeneration. In addition, the functional impact of the deficits is addressed.

Humans↗

PubMed2002

[Higher brain dysfunction in benign childhood epilepsy with centrotemporal spike and atypical benign partial epilepsy of childhood].

Although some recent studies have reported various cognitive impairments and behavioral disorders in children having benign childhood epilepsy with centrotemporal spike (BCECT), it is still commonly believed that BCECT does not cause any definite neuropsychological impairment. In addition, reported impairments range over various cognitive functions, and there is no general agreement on this issue. We performed detailed neuropsychological tests in 17 children with BCECT and analyzed the profiles of their subtests. Atypical benign partial epilepsy of childhood (ABPE) is a type of BCECT in which patients have minor generalized seizures and their EEGs show continuous spike-waves during sleep. We also performed the same tests in five patients with ABPE, and compared the results in the two groups. Neuropsychological tests performed are as follows: Kaufman assessment battery for children (K-ABC), Wechsler intelligence scales for children-revised (WISC-R), Illinois test of psycholinguistic abilities (ITPA), Benton visual retention test (BVRT), Token test, calculation, figure copying task, letter copying task, line bisection task, and line cancellation task. Mental processing composite of the K-ABC and FIQ of the WISC-R were within normal limits in all children with BCECT and ABPE, but were generally lower in ABPE than in BCECT. On the other hand, the profiles of subtests of ITPA in children with BCECT revealed the significant feature of the lower scores on verbal expression (p = 0.013) and auditory sequential memory (p = 0.035). Considering the normal scores in the elementary cognitive functions, such as visual and verbal functions and long-term memory, disturbance in the process of executive functions such as flexibility, fluency, and working memory could cause this characteristic profile. ABPE also showed the similar profile in the subtests of ITPA to that of BCECT. It is likely that both groups of children share the common cognitive dysfunction.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

[The diagnostic value of drawing a clock in geriatrics].

In this study the Clock Drawing Test (CDT) is used in a geriatric department to search for dementia in a population with somatic disorders (N=236). The demented group (N=113) has significant lower scores on every item and on the total score of the scoring method, compared to the non-demented group (N=123). A factor analysis of the scoring method shows that the fourteen items can be grouped into the three groups "contour", "digits", and "hands". A logistic regression shows that "hands" is the most discriminating, although this effect is moderate (sensitivity 59.3%, specificity 75.6%). Considering however that the CDT, compared to other screening tasks, appeals to an unique combination of cognitive functions, including visual semantic memory, working memory, visuospatial skills, attention and executive functions, it can be concluded that this test can contribute to the diagnoses of dementia, besides the traditionally used instruments.

Aged↗

PubMed2006

Neuropsychological functioning in people with ADHD across the lifespan.

ADHD is defined by behavioral characteristics similar to neuropsychological disorders of executive dysfunction. This paper is a literature review of the neurocognitive characteristics of ADHD from early childhood through adulthood. The author addresses the development of the concept of attention and executive function (EF) deficits in ADHD, clinical neuropsychological studies of pre-teenage children, teenagers and adults with ADHD, gender and the role of psychiatric co-morbidity including the relationship of learning disabilities to ADHD, heterogeneity of neuropsychological dysfunctions, experimental neuropsychological studies, the relationship of brain structure to function, psychopharmacology of ADHD, and clinical neuropsychological assessment. The group data clearly supports the hypothesis that executive dysfunctions are correlates of ADHD regardless of gender and age, and these EF deficits are exacerbated by co-morbidity with learning disabilities such as dyslexia. However, there is limited data on children under the age of 5, teenagers from age 13-18, and adults with ADHD over the age of 40. Studies of individual classification of people with ADHD compared to healthy, non-psychiatric controls do not support the use of neuropsychological tests for the clinical diagnosis of ADHD, and indicate that not all persons with ADHD have EF deficits. Some persons with ADHD may have deficits in brain reward systems that are relatively independent of EF impairments. Future research should clarify the multiple sources of ADHD impairments, continue to refine neuropsychological tools optimized for assessment, and incorporate longitudinal, developmental designs to understand ADHD across the lifespan.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Effects of treatment with the atypical neuroleptic quetiapine on working memory function: a functional MRI follow-up investigation.

BACKGROUND: Working memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia. METHODS: Patients were examined by fMRI at baseline and after 12 weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured. RESULTS: At baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre-post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance. CONCLUSIONS: The neuronal networks underlying working memory are clearly altered in schizophrenia. After 12 weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.

Adult↗